The experimental plans focus on two central themes: (a) that comparison of properties of cell lines from long- and short-lived species can suggest hypotheses about pathways that modulate the pace of aging, and (b) that availability of multiple mouse models for delayed aging can test ideas about factors that are indicative of, and in some cases causally connected to, the biology of aging and late-life disease. Aim 1 will evaluate metabolomic and peptide signatures (analytes) from cell lines of rodents, birds, and primates varying in lifespan from 4 to 70 years, to see which analyte signatures are shared among evolutionary clades and are thus likely to be required for evolution of longevity. Aim 2 will develop analyte signatures from plasma and internal tissues of six varieties of slow-aging mice (three drugs, one diet, and two mutations). We predict we will find overlapping signatures in these long-lived mice, suggesting common pathways associated with healthy longevity regardless of the mode of lifespan extension. We predict that some of these biomarkers will also be seen in plasma from exceptionally healthy, long-lived people. We also predict that analytes and signatures found in the cross-species comparisons of Aim 1 will be detectable in slow-aging mice as well. Aim 3 focuses on a collaboration with the Cheminformatics Core, to test sets of drugs in cell lines and in mice. The hypothesis is that the Core-nominated drugs will render mouse and human cells resistant to multiple stresses, and will modify analyte profiles in mice to resemble those of slow-aging mice and long-lived humans. Endpoints for the drug treatment protocols, in cells and mice, will also include those we have previously shown to be characteristic of cells from long-lived species and organs of long-lived mice, including PSMB8, IFN R2- responsive mRNAs, and mitochondrial TXNRD2. We will make extensive use of collaborations with the Consortium's projects on metabolomics and proteomics, and the Cheminformatics Core, and our data will be a rich source of information for the Schork project and the systems biology core as well. We hope to show that analyses of species-specific cellular traits, and materials from slow-aging mice, can greatly enrich the search for pathways, genes, and drugs of special interest for protection of people from the effects of aging and age- dependent diseases.